Abstract
Recurrent and persistent airway infections remain prevalent in patients with primary immunodeficiency (PID), despite restoration of serum immunoglobulin levels by intravenous or subcutaneous plasma-derived IgG. We investigated the effectiveness of different human Ig isotype preparations to protect mice against influenza when delivered directly to the respiratory mucosa. Four polyvalent Ig preparations from pooled plasma were compared: IgG, monomeric IgA (mIgA), polymeric IgA-containing IgM (IgAM) and IgAM associated with the secretory component (SIgAM). To evaluate these preparations, a transgenic mouse expressing human FcαRI/CD89 within the myeloid lineage was created. CD89 was expressed on all myeloid cells in the lung and blood except eosinophils, reflecting human CD89 expression. Intranasal administration of IgA-containing preparations was less effective than IgG in reducing pulmonary viral titres after infection of mice with A/California/7/09 (Cal7) or the antigenically distant A/Puerto Rico/8/34 (PR8) viruses. However, IgA reduced weight loss and inflammatory mediator expression. Both IgG and IgA protected mice from a lethal dose of PR8 virus and for mIgA, this effect was partially CD89 dependent. Our data support the beneficial effect of topically applied Ig purified from pooled human plasma for controlling circulating and non-circulating influenza virus infections. This may be important for reducing morbidity in PID patients.
Highlights
Primary immunodeficiency (PID) diseases are a group of heterogeneous diseases with more than 300 genetically defined markers that affect the function of the immune system.[1,2] In a subset of PID patients, plasma and mucosal immunoglobulin (Ig) levels are reduced or absent, making them more susceptible to infection
We describe a novel CD89 Tg mouse and utilise it to compare the effectiveness of topically applied human polyclonal monomeric IgA (mIgA), IgAM, SC with IgAM (SIgAM) and IgG preparations for the treatment of currently circulating and antigenically distinct influenza virus infections
Generation of human CD89-expressing mice A CD89 Tg mouse line on the C57BL/6 background was generated using a construct containing the full-length human CD89 cDNA followed by an internal ribosomal entry site (IRES) and green fluorescent protein (GFP) cDNA, all downstream of a loxP-flanked mCherry cassette under the control of the CMV promotor (Fig. 1, middle row)
Summary
Primary immunodeficiency (PID) diseases are a group of heterogeneous diseases with more than 300 genetically defined markers that affect the function of the immune system.[1,2] In a subset of PID patients, plasma and mucosal immunoglobulin (Ig) levels are reduced or absent, making them more susceptible to infection. To compensate for reduced antibody production, PID patients may receive ongoing inoculations of plasma-derived intravenous Ig (IVIg) or preparations given by the subcutaneous route, often supplemented with prophylactic antibiotics. Available plasma-derived Igs primarily consist of highly purified polyclonal IgG, obtained by fractionation of plasma pooled from thousands of blood donors. Due to their multi-donor origin, the purified IgGs display a broad range of specificities to viral, bacterial and fungal antigens circulating in the general population. Stable IgG supplementation and antibiotic prophylaxis have successfully reduced persistent infections, such as pneumonia in PID patients,[3] illustrating the benefit of this approach. I.v. injection of human IVIg preparations resulted in 60–70% survival after lethal influenza infection, whereas intranasal (i.n.) IgG administration protected 90% of mice at doses 40–100 times lower,[8] suggesting increased availability and effectiveness of human Ig when applied directly to the mucosal surface
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